Lipoid proteinosis, a very rare autosomal recessive genodermatosis, results in hyaline material deposition in the skin and mucous membrane of various organs leading to multisystem involvement. A case report of a 12-year-old female child is presented here who showed classic features of the disease with generalized thickening, hardening, and scarring of the skin and vocal cord infiltration causing voice changes. The patient also had numerous oral mucosal and dental findings. The knowledge of the clinical features of the disease may help the oral health professional in rendering the appropriate treatment in order to improve the quality of life deteriorated by the disease.

Keywords: Genodermatosis, lipoid proteinosis, oral mucosa, skin

How to cite this article:Mainali S, Nayak R, Gaur S. Oral findings in a child with lipoid proteinosis: A case report and review. J Indian Soc Pedod Prev Dent 2011;29:62-7

Lipoid proteinosis (LP) is a very rare autosomal recessive genodermatosis. It was first reported and described by Urbach and Weithe (dermatologist and otolaryngologist, respectively) in 1929 [1] as "Lipoidosis cutis et mucosae". It was further renamed by Urbach in 1930 [2] as "lipoid proteinosis cutis et mucosae". Since then, it has been known by several terms like, "Urbach-Weithe disease", "lipoglycoproteinosis", "lipid proteinosis", and "hyalinosis cutis et mucosae". It is a multisystem disorder characterized by infiltration of hyaline material into skin, mucosa, and multiple internal organs.

Numerous postulations have been made for etiology of LP. It may represent a lysosomal storage disease due to a defect in single or multiple enzymes. [3],[4] It can occur due to a disturbance in collagen synthesis, as evidenced by decrease in the ratio of type-1 to type-3 collagen associated with a decrease in mRNA for type-1 procollagen. There is also an increase in mRNA for type-4 procollagen resulting in underproduction of fibrous collagens and an overproduction of basement membrane collagens, which tend to deposit in the skin and various other organs-the hallmark of the disease. [4] It may be due to loss of function mutation in the extracellular matrix protein 1 gene (ECM1) on chromosome lq21, resulting in its reduced or absent expression. [2] ECM1 is a glycoprotein that binds to proteoglycan present in the basement membrane, growth factors, and fibrillar protein. So, it has an important function in skin homeostasis. It has biological and physiological role in endothelial cell proliferation, angiogenesis, epidermal differentiation, skin adhesion, binding of dermal collagens, and proteoglycans, and thus wound healing. Because of all these functions, ECM1 is also termed as "biological superglue". [2] It alters normal keratinocyte maturation and differentiation, thus leading to warty hyperkeratosis. Therefore, loss of ECM1 has a profound effect on dermal homeostasis, leading to skin infiltration and scarring.

With about only 300 cases reported till now, [5] including both from live patients and cadaver specimens, the details of etiopathogenesis, course of disease, treatment modalities with long-term follow-up, and prognosis are still debatable.

Case Report

A 12-year-old female patient was referred to the Department of Pedodontics and Preventive Dentistry from the Department of Dermatology with a complain of pain in the lower right back tooth. Pain was occasional, mild in intensity, and aggravated on chewing food. No medication had been taken to relieve the pain. She also had decreased taste perception and burning sensation in the mouth while eating.

Her medical history revealed eruptions of painful pus- or blood-filled blisters on the face when she was 6 months old. The lesions spread to the skin on the entire body. Crops of lesion would appear, heal, and reappear over a period of time. The lesions healed by scarring and in this process, the body parts slowly started becoming hard and stiff. Her voice quality also deteriorated with age and became low and squeaky.

Family history revealed that the child was born of consanguineous marriage (first cousins). No prenatal and natal complications were present. She had a history of delayed milestones and started walking only at the age of 5 years. None of her family members or relatives had similar condition. The two other siblings were normal.

She is studying in standard one and is unable to perform well at school. However, she does not have any difficulty in getting along with her friends. An evaluation by clinical psychology showed that the patient had an IQ level of 71.2, suggesting that she is at the borderline of intellectual functioning with mental age of 7 years 5 months.

On general examination, patient was cooperative, well oriented to time, place, and person. However, she was thin built and her voice was very low and squeaky.

On extraoral examination, generalized "ice-pick" acneiform scars were present all over the body, interspersed between a yellowish waxy skin [Figure 1]. Areas of variable pigmentations were also present, as some lesions were in the process of healing. Only the palms and feet were spared, which were hyperkeratinized [Figure 2] and [Figure 3]. Her elbows and knees were rough, hard, and indurated with wartlike plaques and hyperkeratinization. Diffuse alopecia with varicelliform scarring was present on the scalp [Figure 4]. In areas of no scarring, hairgrowth and hair quality was found normal. The characteristic beaded papules, also known as "moniliform blepharosis", were present on the upper and lower eyelids of both eyes [Figure 5]. Her sclera was icteric and conjunctiva was pale. Clubbing was present on the fingernails and hemorrhagic blisters were found in the nailbed [Figure 2].

Figure 1: Waxy appearance of the skin and pock-like scarring all over the face. In between are the areas of hypopigmentation and lesions in the process of healing

On intraoral examination, mouthopening was restricted, with maximal interincisal opening limited to 14 mm [Figure 6]. However, no abnormalities regarding temporomandibular joint was present, which suggests that normal skin elasticity required for mouthopening was lacking. Soft tissue examination revealed pale mucosa and showed irregular elevations and depressions with pearly nodular deposits throughout. It was hard and indurated. No ulcerations were visible. Tongue was totally depapillated, giving bald and glistening appearance. The lateral border showed clear demarcations of dentition, indicating macroglossia. The lingual frenum was thick, short, and indurated [Figure 7], restricting all its movements. She could not protrude the tongue beyond her lip margins [Figure 8]. Floor of the mouth had yellowish appearance. Hyposalivation was observed. It was confirmed by gently wiping the labial mucosa and leaving for sometime upon which minimal salivary secretion was found [Figure 9]. On palpation, both buccal and labial mucosa were thick, hard, and multiple nodules were felt. Her tongue also had a hard and woody consistency, but nodules were not felt.

Hard tissue examination revealed that the child had permanent dentition. Multiple carious teeth were present, which can be attributed to hyposalivation. Deep dentinal caries was present in 46. Upper right and left lateral incisors were unerupted, which was not consistent with her age. So, an orthopantomogram was advised, which confirmed that both lateral incisors were congenitally missing [Figure 10]. It also showed dental caries involving outer two-thirds of dentin with respect to 46. Lateral cephalogram gave normal findings. No calcifications were seen.

The blood picture showed low hemoglobin, high platelet, and positivity for bile pigments. In view of icterus, a liver function test was performed. Levels of both conjugated and unconjugated bilirubin were high with reversed albumin:globulin ratio. All hepatic enzyme levels were high. Presently, the child's dermatological condition is being treated with topical steroid application. She is also on protein and iron supplements. She will be taken up for the dental treatment when declared fit by the pediatrician.

Discussion

LP usually manifests in early infancy with hoarseness of voice due to vocal cord infiltration. [6] It is then followed by recurrent crops of vesicles, bullae, macules, papules, and nodules on the skin, which are often pruritic. [2] These may be skin-colored or filled with blood or pus. These may appear in any part of the body, eg, face, axillae, neck, hands, scalp, and scrotum. [7] Moreover, the respiratory system, upper gastrointestinal tract, central nervous system, blood vessels, and lymph nodes may also be involved. Infiltration of the scalp often gives patchy or diffuse alopecia. These subside slowly by varicelliform scarring on their own. Gradually, the lesion progresses with recurrent blisters, which again heal to give yellowish waxy appearance. These papules, nodules, or plaques may coalesce to result in diffuse thickening of the skin and mucous membrane. Also, wartlike plaques on elbows and knees are distinguishable more often if subjected to minor injuries or friction. Hyaline deposits have also been described in the conjunctiva, cornea, trabeculum, and retina. [5] Corneal opacities or secondary glaucoma due to infiltration in the trabeculum may appear later. There is a case reported in which bilateral luxation of lens occurred in a patient with LP. The presence of beadlike papules on the margins of both upper and lower palprebral conjunctiva-also known as "moniliform blepharosis"-is the universal sign of this disease. [8] The ocular signs also include epiphora. Nail dystrophy with hemorrhagic blisters on the wrists, fingers, and nailbed is a common finding. The hyaline material is also deposited around blood vessels, resulting in an onion-skin appearance and a small bowel, leading to intestinal bleeding. [8]

Uchida et al. [9] report a case of calcinosis cutis occurring in LP. Calcium deposits were seen in the dermis. Usually, patients with LP are known to have calcification of the temporal lobes or hippocampi in the brain, but cutaneous calcification has not been reported elsewhere. The patient was normocalcemic and normophosphatemic, and the calcium deposits were juxtaposed with hyaline material in the dermis as a dystrophic calcification. The hyaline material in the dermis was thought to be a nidus for calcification. There was no clinical evidence of such calcification in our case.

Intraorally, pearly deposits are seen in the mucosa. The tongue may be hard, enlarged, stiff, and woody. Often, gingival hypertrophy with irregularly thickened lips are found. Bazopoulou-Kyrkanidou et al. [10] describe a 66-year-old man with LP who presented with generalized gingival hyperplasia due to diffuse deposition of hyaline-like material, which they confirmed from the microscopic findings of gingival tissues. Papules have also been seen in one patient in the tongue along with yellowish deposits on the soft palate. The presence of thickened and infiltrated lingual frenum may restrict tongue movements during deglutition and speech. Frequent involvement of salivary glands, usually submandibular and parotid gland, [5] can cause hyposalivation or xerostomia, leading to poor oral hygiene. Oral ulcerations have also been reported by Sargenti et al. [11] in a woman with LP. Whether the oral manifestation or the cutaneous manifestations appear first is not known due to its variable presentation.

Although parental consanguinity has been documented in many cases, LP has been seen in siblings born to nonconsanguinous marriage also. [5] A family was reported in which four siblings (two boys and two girls) born to nonconsanguinous parents had LP. All had the characteristic hoarseness of voice and three had skin lesions.

Mucocutaneous lymphatic system is speculated to play a major role in this disease because the lesions are usually seen in those areas having greater mobility demanding for high plasticity. For example, the flexion and extension of knees, elbows, antecubital fossa; the highly dynamic oral mucosa as a result of eating and speaking. So, a failure of mucocutaneous lymphangiogenesis may underlie the clinical feature of LP. [9] Extracutaneous manifestations like epilepsy, memory loss, schizophrenic behavior, mental retardation, emotional changes, and other neuropsychiatric abnormailities may be seen in some patients.

Mutation analysis can be done for ECM1. [2] Biopsy specimens can be taken from the nodule at the patient's skin, eg, warty nodule of the elbow and from normal skin to use it as a control. In histological examination, disruption and/or duplication of the basement membrane along with deposition of hyaline material in the dermo-epidermal junction, papillary dermis, surrounding capillaries, and around adnexal epithelia, especially the sweat coils can be seen. The hyaline material is eosinophilic, Periodic-Acid-Schiff (PAS) positive, Congo red positive and diastase-resistant, indicating the presence of glycoproteins. [8] Immunofluorescence labeling with anti-collagen antibody shows Type IV and V collagen accumulation and reduction of type I and III collagen around blood vessels. [8] Laryngoscopy can be done if severe dysphonia and dysphagia is present. This is necessary to rule out thickening of the vocal cords, swollen arytenoids and aryepiglottic fold, and hyaline deposits in the larynx, oral cavity, and oropharynx. Intracranial calcification in the temporal lobes or hippocampus can be easily detected by brain computed tomography. Bean-shaped radioopacity can also be appreciated superiolateral to sella turcica in skull radiography. [4]

The most closely resembling condition to LP is erythropoietic protoporphyria. It displays similar skin symptoms, but without oral lesions. Increased values of protoporphyrin in erythrocytes is the key for differentiation. Clinical differentiation can be done by absence of photosensitivity and presence of skin lesions in non-sun-exposed areas in LP. [12] Other differential diagnosis include lichen myxedema, [13] diabetic microangiopathy, [6] amyloidosis, [6] xanthoma, [4] and even battered child. [14] Histologically, amyloid is differentiated by negative staining for PAS and Congo red stain. Some of the ultrastructural changes seen around blood vessels may also resemble abnormalities seen in diabetic microangiopathy.

There is no effective and clearcut treatment regimen for LP. LP compromises the quality of life [7] due to its disfiguring scars and multisystem involvement. Except for the respiratory obstruction in severe cases, the disease in itself is not life-threatening. If the lesions start at an early age, it is found to be self-limiting. [7] However, for esthetic consideration, dermabrasion can be done, as it can become a boon to the patient who is psychosocially affected due to his/her appearance. Chemical skin peeling is another good option. Treatment with dimethylsulfoxide, D-pencillamine, etretinate, intralesional heparin has also been tried. [13] None of them have given a promising result. Laser microlaryngoscopy, mucosal stripping, or dissection of the vocal cords and excision of deposits may be performed to preserve or improve the quality of voice. The patient can also be subjected to logopedic program. [8] In very severe cases, if there is diffuse infiltration of the pharynx and larynx causing respiratory distress, tracheostomy is required. [8] Irrespective of the symptomatic treatment and self-limiting nature of the disease, it deteriorates the quality of normal life. So, it is important that parents of affected children be taken for genetic counselling concerning the risks of having other affected offspring.

As LP extensively involves the oral mucosa and, indirectly, the dentition as well, it is important that the dentist be familiar about it. Also, the oral mucosa exhibits clinical features resembling the oral manifestations of several other systemic diseases. Thus, careful probing into history along with detailed clinical examination followed by necessary investigations is a must to identify such conditions. Moreover, the patient should be put on early preventive measures so that oral complications of the systemic condition do not further deteriorate the quality of life.